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Blood, 1 February 2007, Vol. 109, No. 3, pp. 1026-1033. Prepublished online as a Blood First Edition Paper on October 17, 2006; DOI 10.1182/blood-2006-05-021634. This Article Full Text (PDF) All Versions of this Article: blood-2006-05-021634v1 109/3/1026    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sather, S. Articles by Graham, D. K. Search for Related Content PubMed PubMed Citation Articles by Sather, S. Articles by Graham, D. K. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted May 8, 2006 Accepted September 8, 2006 A soluble form of the Mer receptor tyrosine kinase inhibits macrophage clearance of apoptotic cells and platelet aggregation Susan Sather, Karla D. Kenyon, Jerry B. Lefkowitz, Xiayuan Liang, Brian C. Varnum, Peter M. Henson, and Douglas K. Graham* University of Colorado at Denver and Health Sciences Center National Jewish Medical and Research Center Amgen, Inc. * Corresponding author; email: doug.graham{at}uchsc.edu. Membrane-bound receptors generate soluble ligand binding domains either by proteolytic cleavage of the extracellular domain or alternative mRNA splicing yielding a secreted protein. Mer is in a receptor tyrosine kinase family with Axl and Tyro-3, and all three receptors share the Gas6 ligand. Mer regulates macrophage activation, promotes apoptotic cell engulfment, and supports platelet aggregation and clot stability in vivo. We have found that the membrane-bound Mer protein is cleaved in the extracellular domain via a metalloprotease. The cleavage results in the production of a soluble Mer protein released in a constitutive manner from cultured cells. Significant amounts of the soluble Mer protein were also detected in human plasma, suggesting its physiological relevance. Cleavage of Mer was enhanced by treatment with LPS and PMA, and was specifically inhibited by a tumor necrosis factor converting enzyme metalloprotease inhibitor. As a decoy for Gas6, soluble Mer prevented Gas6 mediated stimulation of membrane-bound Mer. The inhibition of Gas6 activity by soluble Mer led to defective macrophage-mediated engulfment of apoptotic cells. Furthermore, soluble Mer decreased platelet aggregation in vitro and prevented fatal collagen/epinephrine induced thromboembolism in mice, suggesting a potential therapeutic use for soluble Mer in the treatment of clotting disorders. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: E. Thorp and I. Tabas Mechanisms and consequences of efferocytosis in advanced atherosclerosis J. Leukoc. Biol., November 1, 2009; 86(5): 1089 - 1095. [Abstract] [Full Text] [PDF] R. M. A. Linger, D. DeRyckere, L. Brandao, K. K. Sawczyn, K. M. Jacobsen, X. Liang, A. K. Keating, and D. K. Graham Mer receptor tyrosine kinase is a novel therapeutic target in pediatric B-cell acute lymphoblastic leukemia Blood, September 24, 2009; 114(13): 2678 - 2687. [Abstract] [Full Text] [PDF] S. Scutera, T. Fraone, T. Musso, P. Cappello, S. Rossi, D. Pierobon, Z. Orinska, R. Paus, S. Bulfone-Paus, and M. Giovarelli Survival and Migration of Human Dendritic Cells Are Regulated by an IFN-{alpha}-Inducible Axl/Gas6 Pathway J. Immunol., September 1, 2009; 183(5): 3004 - 3013. [Abstract] [Full Text] [PDF] A. Anwar, A. K. Keating, D. Joung, S. Sather, G. K. Kim, K. K. 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Tabas Mertk Receptor Mutation Reduces Efferocytosis Efficiency and Promotes Apoptotic Cell Accumulation and Plaque Necrosis in Atherosclerotic Lesions of Apoe-/- Mice Arterioscler Thromb Vasc Biol, August 1, 2008; 28(8): 1421 - 1428. [Abstract] [Full Text] [PDF] H. Uehara and E. Shacter Auto-Oxidation and Oligomerization of Protein S on the Apoptotic Cell Surface Is Required for Mer Tyrosine Kinase-Mediated Phagocytosis of Apoptotic Cells J. Immunol., February 15, 2008; 180(4): 2522 - 2530. [Abstract] [Full Text] [PDF] W.-F. Fang, J. H. Cho, Q. He, M.-C. Lin, C.-C. Wu, N. F. Voelkel, and I. S. Douglas Lipid A fraction of LPS induces a discrete MAPK activation in acute lung injury Am J Physiol Lung Cell Mol Physiol, August 1, 2007; 293(2): L336 - L344. [Abstract] [Full Text] [PDF]

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